(1) Field of the Invention
The subject of the present invention comprises novel peptidomimetics exhibiting affinity for opioid receptors, possessing the general formula shown in FIG. 1, for gastrointestinal or peripheral administration in the form of a pill, infusion, injection or implant in the treatment of peripheral opioids side effects, particularly constipation or/and respiratory depression.
(2) Description of Related Art
The applications of oral pills or transdermal patches with opiate drugs are the most common treatments of severe acute or chronic pain. These compounds non-specifically distributed over the whole body, beside analgesic effects in the central nervous system, which produce side effects (respiratory depression, constipation, tolerance, sedation, etc.) to such extent that pain treatment is reduced by doctors or refused by the patients. Especially, constipation is the most harmful side effect. The incidence of opioid-induced constipation in patients with non-malignant pain is about 40% [Camilleri M. American Journal of Gastroenterology 2011; 106 (5):835-842]. In one study, a third of patients receiving opioid therapy for chronic pain missed or decreased doses or stopped medication due to constipation [Bell T J, Panchal S J, et al. Pain Medicine 2009; 10(1):35-42].
The available therapies for opioid-induced constipation include oral laxatives, suppositories and the opioid antagonists, naloxone and methylnaltrexone. Because, non-specific laxatives only partially can be effective for opioid-induced constipation, recent developments have focused on medications which specifically target the mu receptor in the gut wall. Two therapies that are currently available are oral naloxone and parenteral methylnaltrexone [McNicol E, Boyce D B, et al. Pain Medicine 2008; 9 (6):634-659].
Naloxone is a competitive antagonist of opioid receptors. Orally, it actively reverses opioid agonist binding at the gut mu receptors. Naloxone undergoes extensive first-pass hepatic metabolism that results in reduction its systemic concentration. Unfortunately, this concentration is not predictable, especially in chronic ill patients often having hepatic problems.
Recently, subcutaneous methynaltrexone has been proposed for the treatment of opioid-induced constipation as a peripherally acting opioid antagonist with restricted ability to cross the blond-brain barrier. [Thomas J, Karver S, et al. New England Journal of Medicine 2008; 358 (22):2332-2343]. Although, methylnaltrexone is quite specifically acting in healthy volunteers, its antagonist against opioid analgesia in chronically ill patients has to be taken into consideration.